PROJECT SUMMARY Mucosal Associated Invariant T (MAIT) cells are a recently identified unique population of innate immune cells with antibacterial activity. Upon activation, MAIT cells can produce cytotoxic molecules, to destroy target cells, or pro-inflammatory cytokines to activate adaptive immune responses. Functionally active MAIT cells are disrupted in those who are HIV+. It is logical to propose that HIV- infection directly weakens the anti-bacterial immune functions offered by MAIT cells, which consequently compromises adaptive immune responses to a bacterial infection, such as Mycobacterium tuberculosis (Mtb). HIV+ individuals have a 20-30 times greater likelihood for developing active Tuberculosis (TB) disease after Mtb infection, when compared to those who are HIV- nave, but this difference cannot be explained by HIV-dependent depletion of CD4 T cells, alone. In collaboration with Dr. Charles Scanga at the University of Pittsburgh, we are developing an SIV/Mtb co-infection model in Mauritian cynomolgus macaques (MCMs) to determine how a pre-existing SIV infection disrupts classical adaptive CD4 T cell responses to Mtb. In this new R21, we will use longitudinal sampling of SIV-, Mtb-, and SIV/Mtb-infected MCMs to test the hypothesis that MAIT cells produce cytotoxic molecules and cytokines after Mtb-infection, but prior to the development of effective adaptive immunity, and that SIV infection impairs the MAIT cell response to infection with Mtb, thus leaving a host more susceptible to development of TB disease. We will test this hypothesis in MCMs who are infected with SIV-only, Mtb-only, or both SIV and Mtb. We will determine if the function of MAIT cells is reduced during the course of SIV infection in the peripheral blood and bronchoalveolar lavage fluid of each individual animal. We will also determine if Mtb-infection rapidly activates MAIT cells and if the frequency of MAIT cells activated by Mtb is dampened in an animal with a pre-existing SIV infection. This study will take advantage of samples available from our ongoing SIV/Mtb co-infection study with Dr. Scanga, while also using dedicated animals to assess MAIT cell function post infection with only SIV or Mtb. If we find that disruption of MAIT cells by infection with SIV weakens anti-bacterial MAIT cell functions, then perhaps we can use MHC-identical MCMs in future studies to determine if adoptive transfer of MAIT cells from SIV-nave to SIV+ animals restores control of early replication of Mtb.